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(Circulation. 1999;99:1047-1053.)
© 1999 American Heart Association, Inc.

Clinical Investigation and Reports

Arterial Flow Conditions Downregulate Thrombomodulin on Saphenous Vein Endothelium

Martin Gosling, PhD¹; Jonathan Golledge, MChir¹; Robert J. Turner, BSc¹; Janet T. Powell, MD

From the Department of Vascular Surgery, Imperial College School of Medicine at Charing Cross, Charing Cross Hospital, London, UK.

Correspondence to Dr J.T. Powell, Imperial College School of Medicine at Charing Cross, Department of Vascular Surgery, Charing Cross Hospital, Fulham Palace Rd, London W6 8RF, UK. E-mail j.powell{at}ic.ac.uk

Background—The antithrombogenic properties of venous endothelium may be attenuated when vein is implanted in the arterial circulation. Such changes may facilitate thrombosis, which is the final common pathway for saphenous vein arterial bypass graft occlusion.

Methods and Results—Using human saphenous vein in a validated ex vivo flow circuit, we investigated (1) the possibility that arterial flow conditions (mean pressure, 100 mm Hg, 90 cpm, 200 mL/min) alter the concentration of proteins involved in regulating thrombosis at the vessel wall and (2) the influence of ion channel blockade on such effects. Concentrations of thrombomodulin and tissue factor were quantified by Western blotting (ratio of von Willebrand factor staining) and immunohistochemistry (as a percentage of CD31-staining area). Thrombomodulin concentrations after 90 minutes of venous and arterial flow conditions were quantified by immunostaining (68.9±4.8% and 41.0±3.0% CD31, respectively; P<0.01) and by Western blotting (1.35±0.20 and 0.15±0.03 ratio of von Willebrand factor, respectively; P<0.01). The ability of endothelial cells to generate activated protein C also decreased from 62±14 to 19±10 ng · min^-1 · 1000 cells^-1 (P=0.01). The significant reduction in thrombomodulin was attenuated if calcium was removed from the perfusate but not by external vein stenting. Inclusion in the vein perfusate of drugs that reduce calcium entry (including Gd³⁺, to block stretch-activated ion channels, and nifedipine) abolished the reduction in thrombomodulin concentration observed after arterial flow conditions. In freshly excised vein, negligible concentrations of tissue factor were detected on the endothelium and concentrations did not increase after 90 minutes of arterial flow conditions, although the inclusion of nifedipine caused the immunostaining to increase from 3.0±0.4% to 8.5±0.7% CD31 (P<0.02).

Conclusions—In saphenous vein endothelium exposed to arterial flow conditions, there is rapid downregulation of thrombomodulin, sufficient to limit protein C activation, by a calcium-dependent mechanism.

Key Words: veins • bypass • thrombosis • ions

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